dipyridamole stress echocardiography in patients with severe left main coronary artery narrowing

Dipyridamole Stress Echocardiography in Patients with Severe left Main

Coronary Artery Narrowing Maria Joao Andrade, MD, Eugenio Picano, MD, Alessandro Pingitore, MD, Nunzia Petix, MD, Vincenzo Mazzoni, MD, Patrizia Landi, and Mauro Raciti, on behalf of the Echo Persantine

International Cooperative (EPIC) Study Group - Subproject “Left Main Detection”

From a population of 2,698 patients (1579 evaluated early after an uncomplicated acute myocardial infarction) who underwent dipyridamole echocap dio@aphy testing (DET) and subsequent coronary angiography, left main (LM) stenosis 250% was prewnt in 73 (61 men and ,iz women, mean age 62 + 8 years). These 73 patients were compared with a control group comprising 100 consecutive coronary patients without LM disease. Both groups were similar regardia mean age, sex, in& dence of previous myocardial infarction, left veu tricular function at rest, and severity of coronmy artery disease by the number of diseased vessels excluding the LM. The proportion of patients w ceiving antiinginal therapy during MT was higher intheLMthaninthenouLMgroup(32vsl40/o;p 4.01). No major complication (severe hypoteu sion, sustained auhythmia, myocauiial infarction or death) occurred during DEL Df 73 patients with LM disease, 68 had positive DEf (sensitivity 93%), dipyridamole time was 7.1 & 3.8 minutes, and the rest+eak stress variation in dipyridamole wall motion score index (1:: normal to 4 = dyskinesia, in an l&segment model)was 0.37 + 0.23; 14 pa tients (19%) were resistant to aminophylline and needed nitrates to resolve ischemia. In the nou l.M @oup, Dg7 was positive in 72% (p <O.OOl vs LM), with a longer dipyridamoie time (9.6 f 5.2 minutes; p tiO.001 vs Ml), lower rest+eak stress wall motion score index variation (0.29 * 0.25; p co.05 vs Ml), and less frequent antidote resistance@%; p ~0.001vsLM). Inthe Lblgroup, severity of LM stenosis, and the extent of associated disease did not influence the results of the test, whereas in the nouLM @oup, dipyridamole time, restqeak stress variation of wall motion score index, and DEf positivity increased with the number of narrowed arteries. DEf is feasible, safe and accurate in patients with LM disease. AC -anow- ic response for LM dig easecouidbereco@dzed,theDEfpositivitypat- tern in the time and space domain was character-

From Istituto di Fisiologia Clinica, Consiglio Nazionale delle Ricerche, Pisa, Italy. Dr. Andrade is a visiting fellow from Hospital De Santa Cruz, Carnaxide, Portugal. Manuscript received July 12, 1993; revised manuscript received and accepted August 16, 1993.

Address for reprints: Eugenio Picano, MD, Istituto di Fisiologia Clinica, Consiglio Nazionale delle Ricerche, Via Paolo Savi, 8, 56100 Pisa, Italy.

ized by a shorter dipyridamoie time, larger extent and severity of the induced dyssynergy, and more frequent antidote resistance than in patients * out LM disease.

(Am J Cauiiol1994;73:450455)

S ignificant left main (LM) stenosis represents the most prognostically important lesion involving the coronary arteries. 1,2 In patients with LM stenosis,

regardless of the presence of symptoms, surgery can significantly improve survival as compared with medical therapy.” Several noninvasive methods are used cur- rently to evaluate patients with coronary artery disease, and to provide an estimation of the extent and severity of coronary artery involvement. The detection of high- risk patients needs particular attention, and several previous studies assessed the usefulness of both exercise electrocardiography testing@ and myocardial stress perfusion scintigraphy with thallium-2017-12 in identifying those with significant LM stenosis. Although associated with high prevalence of positive tests as a rule (sensitivity SO% for stress electrocardiography and >90% for scintigraphy), these methods are unsuccessful in differ- entiating, by specific patterns, patients with LM disease from those with other forms of severe coronary artery disease.9-12 Furthermore, these methods are dependent on the patient’s ability to exercise or on the availability of costly nuclear medicine facilities, or both.

Dipyridamole echocardiogmphy testing (DET) proved to be a feasible, safe and accurate exercise-independent method to evaluate patients with suspected and known coronary artery disease,13-l6 soon after myocardial in- farction17 or after therapeutic procedures.1s-20 The sensitivity of DET increases with the number of diseased coronary vessels (up to 86 to 93% for patients with 3- vessel disease).21 The present study was performed to: (1) evaluate the feasibility, safety and diagnostic value of DET in patients with significant LM coronary artery narrowing, and (2) determine the capability of DET to identify this subgroup of patients with high-risk anatomy.

Ml3HODS Study cohork The study group comprised 73 con-

secutive patients (61 men and 12 women; mean age 62 f 8 years, range 35 to 81) with 30% diameter reduc- tion of the LM coronary artery who underwent DET and coronary arteriography. Patients were selected retrospec- tively from a population of 2,698 (579 evaluated early

450 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73 MARCH 1,1994

TbJBLE I Characteristics of Patients With and Without Left Main Coronary Artery Disease

Left Main Disease

With Without (n = 73) (n = 100)

Mean age (years) 63 + 8 60 + 9 Men (%) 86 91 Prior infarction (%I 57 58 Rest LV function (by echo-WMSI) 1.2 k 0.3 1.2 + 0.2 Number of diseased vessels 1.8 + 1.1 2.0 t 0.9

(excluding LMCA) Dff antianginal therapy (%) 66* 86* Patients receiving therapy 23% 14%

Nitrates 22% 12% Calcium antagonists 18% 11% p blockers 9% 5%

*p <O.Ol. LMCA = left man coronary artery; LV = left ventricular; WMSI = wall motion score

Index.

after an acute, uncomplicated, myocardial infarction) either admitted to our coronary clinic for coronary angiographic evaluation (n = 1,212) or studied in participating centers of the Echo Persantine International Cooperative (EPIC) study, which fulfilled quality control criteria for stress echo reading. 20,21 Data from these patients were compared with those from a ‘ ‘non-LM” group comprising 100 consecutive coronary patients from our in- stitution. No patient who had coronary artery bypass grafting was included in the study.

D@ddmok echocarPogaphy teslhg. DET was performed before angiography in all cases. Patients were instructed to fast for 23 hours before DET, and specifi- cally to avoid coffee and tea. Two-dimensional echocardiographic and 12-lead electrocardiographic monitoring were performed in combination with a dipyridamole infusion of 0.56 mg/kg over 4 minutes, followed by 4 minutes of no dose, and then, if still negative, 0.28 m&g in 2 minutes. Therefore, the cumulative dose was 0.84 mg/kg over 10 minutes. Aminophylline (240 mg), which promptly reverses the effects of dipyridamole, was available. During the procedure, blood pressure and an electrocardiogram were recorded each minute.

Two-dimensional echocardiograms were obtained continuously during and up to 10 minutes after admin- istration of dipyridamole. Commercially available, wide- angle, phased-array imaging systems were used. In the baseline studies, as well as during stress, all echocardiographic views were obtained when possible. Echocar- . dtograms were either recorded only on videotapes or digitally acquired, archived and replayed in a cineloop format, depending on the facilities available at each center. The videotapes at each center were analyzed by the cardiologist-echocardiographist of that center who fulfilled the quality control criteria.2* The readers from each center had completed the learning curve when they began contributing to the central data bank.22 A wall motion score index was derived for rest and peak stress dipyridamole echocardiograms in each patient. The left ventricle was divided into 11 segments21: apex, proximal and distal anterior and inferior septa, and proximal and distal anterior, lateral and inferior walls.

TABLE II Angiographic Findings in Left Main Coronary Artery Disease

No. of Major Coronary Arteries Narrowed

> 50% Diameter LM Patients Non-LM Patients Other Than LM (n = 73) (%I (n = 100) (%)

0 9 (12) 1 21 (29) 40 (40) 2 18 (25) 22 (22) 3 25 (34) 38 (38)

Obstruction In specific coronary arteries

Right 40 (56) 58 (58) Left anterior descending 51 (70) 85 (85) Left circumflex 39 (53) 55 (55)

LM = left main.

Segmental wall motion was graded as: normal = 1; hypokinesia = 2; akinesia = 3; and dyskinesia = 4. The wall motion score index was derived by summation of individual segment scores divided by the number of in- terpreted segments. Inadequately visualized segments were not scored. A test was considered positive when the wall motion score increased by 21 grade at peak stress. However, akinesia changing to dyskinesia was not considered a positivity criterion, because this can be due to passive stretching phenomena rather than to “active” ischemia. In positive tests, dipyridamole time (i.e., the time in minutes from the beginning of drug infusion to the development of stress-induced dyssynergy) was evaluated. In negative tests, the dipyridamole time was ar- bitrarily assumed to be 17 minutes (when aminophylline was administered). In patients in whom aminophylline did not promptly reverse pain or new dyssynergy, intravenous or sublingual nitrates were administered.

Coronary arteriography: Left cineventriculography and selective coronary arteriography in multiple projec- tions were performed in all patients, using either the Jud- kins or Sones technique. Angiograms were inspected for luminal narrowings and classified according to the most severe narrowing in each vessel. Two independent ob- servers, without knowledge of the results of DET, inter- preted coronary angiograms by visual analysis. A significant stenosis was defined as 250% diameter narrowing in the LM trunk and as 275% in the 3 major coronary arteries.

Statistical analysis: Results are expressed as either mean & SD or percentage. Student’s t test was used to compare the means of the continuous variables, and con- tingency tables were analyzed using a chi-square test. Analysis of variance was performed for multiple group comparison. Standard methods were used for calculation of sensitivity and specificity. A p value co.05 was considered significant.

RESULTS Clinical features: Mean age, sex distribution, per-

centage of patients with previous myocardial infarction, and baseline left ventricular function as assessed by rest- ing wall motion score index were comparable in patients with and without LM disease (Table I). The proportion

DIPYRIDAMOLE STRESS ECHOCARDIOGRAPHY 451

of patients receiving antianginal therapy at the time of testing was higher in the LM group (Table I). The type of therapy was similar in the 2 groups regarding nitrates, calcium antagonists and p blockers (Table I).

Angiographic findings: Table II lists the prevalence of associated coronary artery stenoses of 275% reduc- tion in luminal diameter in the 3 major coronary arteries in the 73 patients with LM coronary artery disease and in the non-LM group. Isolated LM disease was found in 9 patients (12%). Excluding LM disease, severity of coronary artery disease assessed by the number of diseased vessels was similar in the LM and non-LM groups (1.81 f 1.10 and 1.98 f 0.90, respectively; p = NS). In a subgroup of 64 patients, severity of LM disease was graded in 3 levels: moderate = 50% (n = 30); moderately severe = 75% (n = 23); and severe = 290% (n = 11).

DiylQdamde B t@iQ$ FEASIBILITY AND SAFETY: No major complication (severe hypoten- sion, sustained arrhythmia, myocardial infarction or death) occurred during DET. Symptoms were not sufficiently severe to require premature interruption of the test in any case. Aminophylline resistance was significantly more frequent in patients with LM disease (19 vs 1%; p ~0.001). Two-dimensional echocardiographic studies were adequate for analysis and of unchanged quality compared with baseline examination in all patients.

DIAGNOSTIC ACCURACY: Results of DET for the LM and non-LM groups are shown in Figure 1. Five patients in the LM group had negative DET (overall sensitivity 93%). Of patients with negative DET, 3 had 75% LM narrowing (2 with associated l-vessel disease [right coronary artery in 1, and left anterior descending coronary artery in the other], and 1 without significant con- comitant coronary lesions) and 2 had 50% narrowing (1

Left Main Sensitivity of DET

I (n=22)

q - Aminophylline Resistance @ - Significant vs all other groups

FlWRE l. Bar graph showing sanqltlvlty of dipyridsmole echocard- testing (DEV in patie*= 2: +fassdWhandbftmain(Wconmary . Astehk hdii p eO.OS in all inbrgroup comparisons

with associated 3-vessel disease, and the other with an associated significant stenosis in the left circumflex artery). None of these five patients had chest pain during the test, and only 1 had significant electrocardiographic changes (ST-segment depression 21 mm 80 ms after the J point). In the non-LM group, sensitivity was 72% and increased with the number of significantly diseased vessels (Figure 1).

Dipyridamole time was 7.1 f 3.8 minutes in patients with LM coronary artery disease and 9.6 f 5.2 minutes in the non-LM group (p <O.OOl): 7.1 f 3.9 minutes for 3-vessel disease, 8.4 + 4.5 minutes for 2 vessel-disease, and 12.7 + 5.1 minutes for l-vessel disease. Variation of wall motion score index between rest and peak stress was 0.37 f 0.23 for the LM group and 0.29 & 0.25 for the non-LM group (p ~0.05): 0.18 f 0.26 for l-vessel disease, 0.34 f 0.22 for 2-vessel disease, and 0.38 f. 0.23 for 3-vessel disease (Figure 2). In patients with LM disease, the presence and number of associated significant stenoses in other major coronary vessels did not influence the values of dipyridamole time or variation in wall motion score index (Figure 3). Values for both dipyridamole time and variation in wall motion score index between rest and peak stress were significantly

FlGuRE1.Bargtaph!showlngle+ammm vdatlon in wall motiiscomindax(wMsI),andvaluaaofdl~ ti~f0r4study~p9.~=kftmain;V=ves&.

452 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73 MARCH 1,1994

higher for patients with LM and 3-vessel disease than for those with l- and 2-vessel disease (p ~0.001).

CAPABILITY OF DIPYRIDAMOLE ECHOCARDIOCiRApHY TESTING TO IDENTIFY LEFT MAIN CORONARY ARTERY DISEASE BY SPE- CIFIC PATTERNS: We hypothesized that because of the localization of stenosis proximal to the left anterior descending and circumflex coronary arteries, patients with LM disease could be characterized by an earlier appearance or a larger area, or both, of new abnormal wall motion (due to simultaneous ischemia in the vascular distribution of both coronary vessels) than that in those with other forms of coronary artery disease. Patients who fulfilled Y of 2 criteria (dipyridamole time 26 minutes and variation in wall motion score index 20.36) were considered at high risk for LM disease. Therefore DET correctly identified significant LM disease in 55 of 73 patients (75%/o), with a specificity of only 40% (60 of 100 without LM disease also fulfilled 1 criterion). How- ever, if severe coronary artery disease (LM or 3-vessel disease) was considered, the criteria were fulfilled in 79 of 100 patients (79%) with a specificity of 53% (29 of 62 without severe disease also fulfilled 1 criterion). Al- though the severity of LM coronary obstruction did not

appear to have a major influence on the frequency or pattern, or both, of abnormal DET, none of 11 patients with 290% narrowing of the LM coronary artery had negative DET, and this subgroup had the shortest dipyridamole time and most marked variation in wall motion score index (50 to 75% LM stenosis: dipyridamole time 7.4 f 4.2 minutes: and variation in wall motion score index 0.35 + 0.25; vs 290% LM stenosis: 6.3 f 3.0 minutes and 0.41 + 0.16, respectively) (Figure 4).

DISCUSSION The results of this study conlirm the value of DET

for the recognition of coronary artery disease, and show that it is safe and well tolerated in patients subsequent- ly proved to have significant LM stenosis. Although no pathognomonic response for LM could be detected, the DET positivity pattern in the time and space domain was characterized by a shorter dipyridamole time, and a def- inite trend toward a larger extent and severity of the induced dyssynergy in comparison with that in patients with non-LM disease. Antidote resistance was also more frequent in patients with LM disease.

In this study, the great majority of patients with LM disease had positive DET Sensitivity of the method in

,eft Main - Influence of Associated Disease Extenl

098

5; 0,7

2 1;; p= 0.08 d T T

O-IV 2-3V (n=30) (n=43)

2 14

g 12

g 10 .-

c: 8

s

; 6

ii! 4

2

.- a"

2

0

o-lV 2-3V (n=30) (n=43)

FKiuRE 3. Bar @@ @IOwing influence of extent of ass06 FlGURE4.Bar@aphsihowinginfluenceofleftmaindii -wartery-on vadatha in wall motion severity en varlaths in wall moth score index (WhlS I) score hh (WMS I) and dipykhnole time. V = vessel. and dipyMamole time.

Left Main - Influence of Disease Severity

097 3 1 (/3 W -

1 I p = ns T

50 -75% I 90%

(n=53) (n=ll)

2 14

.g 12

; 10 .-

? 8 s

E 6

4 4 'r .j? 2

n 0

50 -75% L 90%

(n=53) (n=ll)


this high-risk cohort was high and comparable to that reported for myocardial scintigraphy.8-12 At least two of 5 false-negative results can be related to the presence of moderate coronary stenoses (50%), in which case, accuracy is known to decrease due to variable levels of functional significance of the stenoses.*s One negative test was performed under heavy (p blockers plus calcium antagonists and nitrates) antianginal therapy, which may protect against dipyridamole-induced ischemia.24 Finally, coronary hypertone at the time of coronary angiography may lead to overestimation of the organic stenosis in LM disease *x*~ possibly explaining why the lesion was “missed” by DET, which only senses the organic component of the stenosis.27,28

ln&ilityuf~~testing tounecluivocdlyeleftm&wWefound no specific positivity pattern for LM disease, and in particular, none that could distinguish between LM and 3- vessel disease. This finding was not surprising for several reasons: (1) LM disease is associated frequently with 2- and 3-vessel disease (in this study, 59% of patients with LM stenosis had multivessel disease). The extent, severity and location of coronary arterial narrowings distal to the LM artery significantly modulate the ischemic response, probably in a more important way than does the severity of LM disease itself. (2) The same physiologic impact for induction of ischemia can result from different anatomic patterns (e.g., isolated LM disease can be indistinguishable from LM equivalent). Furthermore, as with all physiologic testing, DET results are tightly correlated with coronary flow reserve impair- ment,29,30 which is linked only loosely to the angio- graphically assessed stenosis in unselected populations.“’ (3) Ischemia and asynergy are considered absolute end points of DET. Therefore, termination of DET immedi- ately after the appearance of the first asynergic territory overshadows less compromised territories and explains the tendency of DET to underestimate more severe forms of coronary artery disease.

Comparison with previous studies: To our knowledge, this study represents the largest series published to date describing the results of an imaging technique in patients with significant LM stenosis, and the ftrst one in which stress echocardiography was used. Previous studies assessed the usefulness of exercise electrocardiographic testingCs,s2 and myocardial stress perfusion scintigraphy’-i2 in the noninvasive identification of patients with significant LM disease. The present data show that the sensitivity of DET for detecting coronary artery disease in LM patients is higher than that of exercise electrocardiographic testing and comparable to that of myocardial stress perfusion scintigraphy. More- over, DET provides the integration of the most important information derived by those 2 techniques (i.e., an accurate measurement of the time to ischemia [derived by exercise electrocardiographic testing], and the geo- graphic localization and extent of myocardial ischemia [obtained by scintigraphy]). However, as with exercise electrocardiographic testing and scintigraphy, the response to DET does not appear to be sufficiently specific for definitive identification of LM disease.

Study limitations: Anti-ischemic therapy can lower the sensitivity of various diagnostic tests, including DET,24 in addition to modifying the dipyridamole time and variation in wall motion score index by influencing the extent and threshold of ischemia. Therefore, the significant dissimilarity between the 2 groups regarding therapy may have affected the study results. However, this is the common situation found in routine clinical practice where patients, especially those thought to have more severe forms of disease on the basis of clinical pre- sentation, usually receive variable antianginal medica- tions, even at the time of diagnostic testing. The addition of atropine to DET, by increasing myocardial oxy- gen demand through chronotropic stress and reducing flow supply through a shortening of the diastolic phase, could have contributed to further enhancing sensitivity in the detection of coronary artery disease.33

In conclusion, DET is feasible, safe and accurate in patients with LM disease. Although no pathognomonic response for LM disease could be identified, the DET positivity pattern in the time and space domain was characterized by a shorter dipyridamole time, larger extent and severity of the induced dyssynergy, and more frequent antidote resistance than was that in patients without LM disease.

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dipyridamole stress echocardiography in patients with severe left main coronary artery narrowing

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